We propose to continue stuies on the synthesis and evaluation in selected enzyme systems of pteridines and related heterocycles which may prove of value both as pharmacological agents (neoplastic, bacterial, protozoal and filarial diseases) and as biochemical tools. Target 2,4-diaminopteridines and azapteridines will be evaluated as inhibitors of dihydrofolate reductase from normal rat liver, murine leukemia (L1210) cells, trypanosomes (T. crusi, T. rhodesiense), bacteria (L. casei), and filaria (D. immitis). Studies will be continued on the activity of selected heterocycles as substrates for and/or inhibitors of xanthine oxidase, aldehyde oxidase, and adenosine deaminase in vitro. Synthetic biopterin and neopterin analogs will be investigated as cofactors for and/or inhibitors of tetrahydropterin-requiring aromatic amino acid hydroxylase systems; such compounds may prove useful not only in biochemical studies, but also as potential adjunctive agents for the pharmacological managements of conditions possibly associated with the dysfunction of hydroxylase systems (e.g. certain hypertensive states, Parkinson's disease). We will initiate collaborative studies on the cytotoxic effects in vitro of our target compounds on mammalian fibroblasts, Schistosoma mansoni, and the filarial worm Brugia pahangi. Our studies on the development of new synthetic methodologies in heterocyclic chemistry will be continued.